Goals Basic defect Pathophysiology Clinical i l signs and symptoms Therapy

Transcription

1 CYSTIC FIBROSIS Lynne M. Quittell, M.D. Director, CF Center Columbia University

2 Goals Basic defect Pathophysiology Clinical i l signs and symptoms Therapy

3 What is Cystic Fibrosis? Chronic, progressive and life limiting autosomal recessive genetic disease characterized by chronic respiratory disease, pancreatic insufficiency, elevation of sweat electrolytes and male infertility

4 Clinical Presentation Chloride channel defect in exocrine glands Thick secretions Recurrent pneumonia Pancreatic insufficiency High salt content in sweat Male infertility

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6 Wehe dem Kind, das beim Kuss auf die Stirn salzig schmekt, er ist verhext und muss bald sterben Woe is the child who tastes salty from a kiss on the brow, for he is cursed, and soon must die

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8 Genetics of CF Most common lethal genetic disease in Causasians 30,000 affected individuals in US 27,000 in Europe CFTR - camp regulated chloride channel located in apical membrane of glandular epithelium Encodes for a protein of 1480 amino acids Defective ect e ion transport t Class defects Long arm of chromosome #7 D508 most common mutation 1000 identified mutations

9 Ion Transport

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11 The Cystic Fibrosis Airway Bacteria Phagocytic Cells Lyso zym e L actoferin, SLPI P h os ph o lipa se A2 S e cret ory IgA S P-A, S P - D, N O hbd-1, h B D- 2, L L-3 Cl- Na+ CFTR Mucociliary Clearance Mucus Plug NFκβ IL-8 cus Mu Neutrophils Cl-Na+ Acquired Immunity Used with permission - R. Gibson, 2004.

12 Molecular Consequences of CFTR Mutations Normal I II III IV V No synthesis Block in processing Block in regulation Altered conductance Reduced synthesis Nonsense G542X Frameshift 394delTT Splice junction G 1G >A Missense AA deletion ΔF508 Missense G551D Missense Missense R117H A455E Alternative Splicing kbC >T

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16 The sweat test ( Chloride) Normal Under 40 meq/l Borderline meq/l Positive Over 60 meq/l

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19 Airway Mucous Plugging, Infection, and Inflammation in Cystic Fibrosis Used with permission J. Wagener, 2004.

20 CF Lung: End-Stage Bronchiectasis 3 2 1

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22 CF Pathophysiology CFTR gene defect Defective ion transport Airway surface liquid depletion Defective mucociliary clearance Mucus obstruction Infection Inflammation

23 Age-Specific Prevalence of Respiratory Infections in CF Patients, 2008 HBQ 6/06 HBQ 6/06 Source: Cystic Fibrosis Foundation Patient Registry, 2008 Annual Data Report

24 Birth 1st Pa + culture Natural History of Acquisition of Pseudomonas aeruginosa 2nd Pa + culture Pa negative culture Persistently tl Pa + cultures Mucoid P. aeruginosa Intermittent t Chronic infection infection Eradication Pulmonary Exacerbations Chronic Suppressive Therapy

25 Evidence of increased inflammation in BALF of infants with CF CF 80 Controls % Neutrophils IL-8 (ng/ml) Uninfected Infected Uninfected Infected (n = 23) (n = 27) (n = 23) (n = 28) Adapted from Muhlebach et al. Am J Respir Crit Care Med 1999; 160:

26 CF Lung Function

27 Presentation (CF PANCREAS) C F P A N C R E A S Chronic respiratory disease Failure to thrive Polyps Alkalosis, metabolic Neonatal intestinal obstruction Clubbing of fingers Rectal prolapse Electrolyte in sweat Aspermia / absent vas deferens Sputum S.aureus/P.aeruginosa

28 Signs and Symptoms of Pulmonary Exacerbation Increased cough Increased sputum New chest findings rales, wheezes Weight loss Decreased exercise School/work tolerance absenteeism Decreased FEV1 Increased dyspnea down 10% New radiographic findings

29 CF mild disease: hyperinflation, increased markings CF advanced disease: with bronchiectasis

30 High-Resolution Inspiratory and Expiratory CT Scan in 12 year old Used with permission - C. Milla, 2004.

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32 CF: Pulmonary Complications

33 Hypertrophic osteoarthropathy Clubbing Periostial new bone formation Proliferation of skin and osseous tissue at distal parts of extremities

34 Exacerbations Contribute to the Deterioration of Lung Function 100 After treatment 80 FEV 1 (% predicted) Exacerbations 0 Used with permission from P. Flume. Age (y) Acute exacerbations with some reversibility Chronic decline

35 CF: Respiratory management Regular visits to CF Center Airway clearance Mucus thinners (DNase, hypertonic saline) Antibiotics( PO-IV-Aerosol) Anti inflammatory agents

36 Airway Clearance CPT Vest Flutter ACB

37 Airway Clearance Chest Physical therapy Vest mechanical percussion Flutter, Acapella Breathing techniques : ACB Exercise

38 Mucolytic agents Recombinant DNase Hypertonic saline

39 Treating Airway infections Prophylactic treatment prevent colonization Exacerbations improves lung function reduces inflammation decreases bacterial density First isolates may delay colonization

40 Antibiotics Oral IV Aerosolized Special Considerations: Volume of distribution Sensitivities Drug Interactions Side effects

41 Phase 3 TSI Trial: Mean Relative Change in FEV 1 % Predicted Mean Relative Cha ange in FEV 1 % Predicte ed On Drug On Drug On Drug Week TSI (n = 257) Placebo (n = 262) Ramsey BW et al. N Eng J Med 1999 Konstan and Saiman NACFC 2009; Plenary Session II

42 Anti-inflammatory inflammatory Rx Steroids inhaled v oral Ibuprofen Macrolides ISSUES Safety Adherence? Delay in progression of the disease

43 Relative Change in FEV 1 % Predicted 5 Day 168 Treatment t Effect: 6.21% (p=0.001) 4 2 Azithromycin Day 168 Δ: 4.44% 0-2 Placebo Day 168 Δ : -1.77% Study Day

44 CF PFT s

45 CF: Gastrointestinal Disease Pancreatic insufficiency/malabsorption Lipo-soluble vitamin deficiency (ADEK) Failure to thrive - hypoproteinemia i and edema Neonatal intestinal obstruction (15%) Recurrent distal intestinal obstruction Biliary stasis - portal hypertension 2-5% pts

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47 CF: Pancreas- malabsorption

48 40 Median Predicted Survival Age, (with 95 percent confidence bounds) Med dian Surviv val Age (Ye Years) '85 '86 '87 '88 '89 '90 '91 '92 '93 '94 '95 '96 '97 '98 '99 '00 '01 '02 '03 '04 Year As of August 2006, the median predicted d survival is 36.5 years '05 for 2005.

49 Newborn screening all States in US & EU Advantages Early diagnosis and intervention Genetic screening Improved nutrition Risks False results Cost and anxiety CFMA Models IRT/IRT IRT/DNA

50 SUMMARY Need to understand the pathophysiology of CF lung disease in young patients Need to understand the risk/benefit ratio of new treatments Adherence Window of opportunity Changing landscape

51 Pediatric Asthma Reversible airway obstruction Triggers: allergies, weather changes, exercise, environmental triggers Cough, wheeze, shortness of breath Lower airway obstruction

52 Bronchiolitis RSV Mucous plugging secondary to airway debri Minimal reversibility Obstructive pattern